Acute HIV infection is accompanied by a wave of lymphocyte activation and depletion that likely includes both infected and uninfected cells. The mechanisms for lymphocyte activation and the mechanisms for cell loss are not well explained, but are at the core of viral pathogenesis. The ability of HIV infection to drive the depletion of lymphocytes that are mounting anti-viral immune responses may be important in the failure to contain the initial viremia, and may ead to the establishment of persistent infection with chronic disease. We believe that FasL, whose expression increases during viral infection, is a principal mediator of lymphocyte depletion, especially within the Fas receptor expressing memory cell population, and may also influence the acute infection by promoting the expression of pro- inflammatory cytokines that increase the level of virus replication. In this proposal, we postulate that these same mechanisms we have implicated in the pathogenesis of acute SIV infection, may also work to blunt pre-existing immunity that was achieved through vaccination. Should FasL have a major role in overcoming the protective effect of vaccination, it will be an important mechanism for evading host immunity and should be considered alongside sequence variation and other mechanisms that may account for potential vaccine failures. Our experimental approach is to block the activity of FasL during acute SIV infection of macaques, by injecting a monoclonal antibody against this protein. In Preliminary Studies, we provide evidence for the activity of anti-FasL in macaques, showing that treatment of monkeys only during the interval of acute infection, increased cellular and humoral immune responses to virus and extended the survival times after SIV challenge. In the proposed research, we start by immunizing macaques against SIV and reference antigens, then challenging them with SIV infection with or without anti-FasL treatment. The experimental plan also includes studies on gamma/delta T cells and B cells, population that respond to SIV infection but are not susceptible to virus infection. These studies provide a way to define the impact of infection and FasL on cells that are not directly infected by SIV. A comprehensive plan for assays of immune responses, cytokine production and virus burden in blood and lymphoid tissues allows for testing of the main hypothesis about FasL-mediated cell death and will also show the impact of blocking FasL on virus dissemination and cytokine production that might signal alternate mechanisms of action. In future, it may be possible to design vaccine antigens that elicit protective immune responses without driving the production of FasL. These antigens may in and of themselves, elicit stronger responses and provide the host with an important kinetic advantage after natural exposure to HIV. LAY SUMMARY: HIV infection might evade the protective activity of vaccines, by triggering a mechanism for immune cell destruction and loss of protection against HIV disease. Other mechanisms for vaccine evasion include mutation, that changes the chemical structure of viral proteins, and interference with immune cell recognition. By defining the role for immune cell destruction in vaccine evasion, we contribute to a complete understanding of potential mechanisms for vaccine failure that will be used to improve the design and testing of candidate HIV vaccines.